DK165438B - TABLETS CONTAINING A QUICK DISPERSIBLE CORE - Google Patents

Description

in

DK 165438 B

The invention relates to tablets containing a fast dispersible core, such as medical tablets, which are intended for dispersion in water to form a potable mixture.

5 Many options exist for performing oral medical treatment, and each of these options is suitable under certain specific conditions. In addition to the solid dosage forms, such as tablets and capsules, there is also a growing need for liquid, drinkable preparations. This is especially true for older people and children, and when large doses of the drug are needed frequently and / or over long periods of time.

Drinkable preparations can sometimes be dispensed to the patient as they are already in liquid form, in solution, suspension or emulsion. This always has obvious transport disadvantages, and in addition, many drugs tend to disintegrate rather quickly.

A good alternative is to deliver the drug in a particularly solid formulation which, when immersed in water, will rapidly disintegrate to form a mixture that is homogeneous and comfortable enough to be drank. Examples are effervescent tablets and dispersion tablets. The former are due to the reaction of hydrogen carbonate or carbonate with an acid or to other excipients capable of developing gas upon contact with water. The latter depend on the presence of disintegrants with the ability to swell with water. Because many drugs are incompatible with hydrogen carbonate and / or with 30 acids, the dispersion tablets are the most commonly used of the two kinds of tablets. An example of the latter is disclosed in GB Patent 2,067,900, which relates to a dispersible tablet containing, as a medicament, trimethroprim and sulphamethoxazole and as a disintegrant crosslinked polyvinylpyrrolidone.

Another problem that arises independently of the problem of making a potable preparation is

DK 165438 B

2 to protect certain active substances from loss of substance, strength and / or physical / chemical properties due to contact with the atmosphere, recrystallization and / or sublimation. To this end, several solutions have been provided, such as sugar-coated, film-coated and compression-ion-coated tablets, capsules and microcapsules. The latter are quite expensive to manufacture and also tend to lower bioavailability, while the other forms of protection that have hitherto been devised are almost per capita. definition could be considered incompatible with the principle of the dispersible tablet, ie. the ability for rapid disintegration in water. Therefore, no coating of dispersible tablets has been described previously.

U.S. Patent No. 3,019,169 relates to a tablet consisting of a core containing a first active compound and a shell containing a second active compound, which two active compounds are not compatible by physical composition. The tablet is for oral administration without prior disintegration in water. This is in contrast to the present invention where the active compound is present only in the core and where the tablet must be disintegrated in water prior to ingestion.

DE Publication No. 1,81,809 mentions 25 different tablets which contain at the core an active compound enclosed by a compression coating, also containing an active compound. In the document, nothing is mentioned about compression-coated tablets, let alone any of the properties of such tablets (for example, the integration time). Furthermore, the active compounds are not characterized by any special (physico-chemical) properties.

It has now surprisingly been found possible to combine the desired properties with rapid disintegration in water and protection from the harmful effects described earlier.

DK 165438B

Accordingly, the invention relates to tablets containing a rapidly dispersible core which are characterized in that the core containing the active compound (s) which is prone to sublimate and / or recrystallize is coated with a compression coating which also is rapidly dispersible and containing one or more disintegrants selected from a. crosslinked polyvinylpyrrolidones 10 b. crosslinked sodium carboxylmethyl celluloses c. sodium starch glycolates d. Formaldehyde caseins where the finished tablet is capable of disintegrating in 0 water at 20 ° C within three minutes for a homogeneous drinkable 20 dispersion with a particle size of less than 0.71 mm.

Examples of the disintegrants for use in the coating are: a. Crosslinked polyvinylpyrrolidones (such as POLYPLASDON-XL®, KOLLIDON-CL®); b. cross-linked sodium carboxymethyl celluloses (such as Ac-Di-Sol®); c. sodium starch glycollates (such as PRIMOJEL, EXPLOTAB); 30 d. Ion exchange resins such as AMBERLITE-IRP-88 or microcrystalline celluloses (such as AVICEL® PH-101, PH-102); f. compressible starch species (such as STARCH-1500; 35 g. starch and modified starch species; h. alginic acid and derivatives thereof; 1. formaldehyde casein (such as ESMA-SPRENG).

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In particular, cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethyl cellulose and sodium starch glycolate have proven to be very useful.

The composition of the core may be the same as the composition of conventional known dispersible tablets within the pharmacy. In addition to the active substances and their integrating agent, it may contain other substances commonly used in the pharmaceutical, such as binders (e.g., methylcellulose, polyvinylpyrrolidone), granulating aids (e.g., magnesium carbonate), lubricants (e.g. silica preparations), lubricants (eg magnesium stearate), fillers (e.g. lactose and microcrystalline cellulose), flavor enhancers and dyes.

The active substance (s) constitute a maximum of 70% by weight of the core, preferably not more than 65%.

In addition to the disintegrants, the tablet's compression coatings may contain other pharmaceutical excipients such as binders, lubricants, lubricants, fillers, flavor enhancers and colorants.

It will be appreciated that the dispersible coating which protects the core can itself be sensitive to atmospheric moisture, against which it can be protected by known methods in the art, such as bubble gaskets.

The tablets of the invention are particularly suitable for active substances which are prone to sublimation and / or recrystallization.

A particular example of such an active substance is cyclandelate.

Cyclandelate, a well-known vasoactive substance, is found primarily in medical use in elderly patients.

Over the many years that this drug has been used, its scope has been gradually expanded and the recommended daily dose increased, as is the duration of treatment. Today, patients are taking cyclandelate

DK 165438 B

5 daily doses of up to 1600 mg for several consecutive years. As cyclandelate tends to sublimate and recrystallize upon contact with the atmosphere, its present formulations are sugar-coated tablets and capsules. When the need for a potable preparation was expressed, the dispersible tablets of the invention proved to be very convenient.

Therefore, tablets containing cyclandelate are a preferred embodiment of the invention.

The cyclandelate-containing tablets prepared according to the invention have a preferred content of 400 -1200, preferably 800 mg of cyclandelate.

The idea of compression coating itself is pretty old, going back to P.J. Noyes British Patent 859,996 (1896). In 1937, F. Kilian, a German inventor, was granted British Patent 464,903 on a combination of two synchronously running machines for the production of compression-coated tablets. The principle of this patent is applied to the Manestry Dry Cota apparatus available today, while Kilien himself developed another idea with a single rotary press designed to carry out the coating step alone, which press is today sold as Prescoter type of RUD. This machine was used in the process of the invention, but because it (like all other machines available for compression coating) was only capable of processing much smaller cores than required for the dispersion tablets containing 800 mg of cyclandelate (which cores had a diameter of about 14 mm and a thickness of more than 8 mm), a special adaptation of the Prescoter had to be performed.

In Kilian's Prescoter, the cores are fed to a rotating core collecting plate from a vibrating food container through a glass tube. In the adapted apparatus 35, the cores are first fed from the food container to a core delivery plate, provided with recesses for receiving

DK 165438 B

6 of the cores, which plate is driven by a stepper motor running synchronously with the press. The food container is connected to the plate via an oblique, open abrasive consisting of a series of thin metal bars (preferably stainless steel).

5 From the core delivery plate, the cores fall onto the core collecting plate via a vertical tube. The apparatus is shown in FIG. 1/2 and 2/2, showing the adapted part of the apparatus from above and from the side respectively.

In the figures, 1 is the vibrating food container, 2 is the open slit, 3 is the core delivery plate, 4 the stepper motor, 5 the vertical tube and 6 the core collecting plate. In addition, a photocell 7 is installed and connected with appropriate control equipment for stopping the tablet machine when no cores are delivered.

The tablets coated by this custom Prescoter machine have a total outer diameter of approx. 18 mm and a thickness of approx. 9 mm. The compressed 20 coatings are approx. 1.5 mm thick.

The following examples are illustrative of the invention.

Example 1

A dispersible tablet core was prepared as follows: 50 kg of cyclandelate having a particle size of less than 0.71 mm (25 mesh) was mixed with 1.25 kg of magnesium carbonate and 9 kg of aqueous 1.2% methylcellulose.

The mass was granulated and dried and then passed through a swinging screen with a mesh width of 0.71 mm (25 mesh). The granulate was then mixed with: PRIMOJEL (sodium starch glycollate 2.5 kg 35 KOLLODON CI 2 (crosslinked polyvinylpyrrolidone) 5.38 kg AVICEL ® PH-102 (microcrystalline cellulose) 11.6 kg

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7 LEVILITE ® (silica) 1.9 kg AEROSIL 200 V® (silica) 1.05 kg

Magnessium stearate 0.38 kg

Saccharin sodium 0.94 kg CAPSAROMA (natural peppermint aroma mc-92505) 0.94 kg

This mixture was then pressed into dispersible cores that were flat with a faceted edge and had a diameter of 14 mm, a thickness of 8.3 mm, a weight of 1215 mg and a content of 800 mg of cyclandelate. The hardness, tested in a Schleuni-ger type 2-E hardness tester, was 60 newtons. These cores completely disintegrated in 15-25 seconds when immersed in 30 ml of water at 20 ° C.

A number of these cores were stored at room temperature and examined periodically.

Within three months there were no visible changes.

Between 3 and 6 months, a fluffy white, white deposit appeared on the surface of the core, which, after further storage (between 6 and 12 months), densified to form a coherent layer. Additional storage resulted in the individual cores sticking together.

The deposition consisted of pure cyclandelate, which was sub-limed from the core and recrystallized on its surface. It was not dispersible.

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Example 2

A mixture for a dispersible compression coating was prepared by admixing (wt%): 5 KOLLIDON CL® (crosslinked polyvinylpyrrolidone) 19.5% AVICEL® PH-102 (microcrystalline cellulose) 69.0% AEROSIL 200 V® (silica) 0.5% Magnesium stearate 1.0%

Lactose DC 10 (direct compressible lactose) 10.0%

This mixture, together with the cores made according to Example 1, was fed to the Kilian Prescoter apparatus, specially adapted as described previously. The obtained dispersible compression-coated tablets had an outer diameter of 18 mm, a thickness of 9 mm, and the coating was 1.5 mm thick and the total weight was approx. 2.28 g. When these tablets were immersed in 20 ml of water at 20 ° C, they completely integrated in less than 90 seconds to form a homogeneous potable suspension after simple stirring. The amount of dissolved material, examined in a Roche freeabilator (25 rpm for three minutes), was less than 1%.

A number of these completely coated tablets were stored and examined periodically.

At room temperature, there were no visible changes within 12 months. At 37 ° C, after nine months, there were still no visible changes and no changes in water dispersibility, but the coating, which initially did not contain cyclandelate, now contained 2-3% of this substance.

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Example 3

A mixture for a dispersible compression coating was prepared by admixing (wt%): 5 KOLLIDON CL® 19.5% AVICEL® PH-102 64.0% AEROSIL 200 V® 0.5%

Magnesium stearate 1.0%

Lactose DC 10 10.0% 10 Polyethylene Glycol 6000 5.0%

This mixture, together with the cores, prepared according to Example 1, was fed to the Kilian Prescoter apparatus, which was specially adapted as previously described. The obtained dispersible compression-coated tablets had the same properties as given in Example 2.

Example 4

A mixture for a dispersible compression coating was prepared by admixing (wt%): KOLLIDON CL® 19.5% AVICEL® PH-102 64.0% AEROSIL 200 V ® 0.5%

Magnesium stearate 1.0%

Lactose DC 10 10.0% LHPC LH 11 (low-substituted hydroxypropyl cellulose) 5.0%

This mixture, together with the cores made according to Example 1, was fed to the Kilian Prescoter apparatus, which was specially adapted as described previously. The obtained dispersible compression-coated tablets had the same properties as given in Example 2.

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Example 5

A mixture for a dispersible compression coating was prepared by admixing (wt%): 5 KOLLIDON CL® 19.5% AVICEL® PH-102 50.0% AEROSIL 200 V® 0.5%

Magnesium stearate 1.0%

Lactose DC 10 29.0% 10

This mixture, together with the cores made according to Example 1, was fed to the Kilian Prescoter apparatus, which was specially adapted as described previously. The obtained dispersible compression-coated tablets had the same properties as given in Example 2.

Claims (9)

1. Tablets containing a rapidly dispersible core, characterized in that the core containing the active compound (s) which is prone to sublimate and / or recrystallize is coated with a compression coating which is also rapidly dispersible and which contains one or more disintegrants selected from a. cross-linked polyvinyl pyrrolidones 10 b. cross-linked sodium carboxyl methyl celluloses c. sodium starch glycolates d. ion exchange resins or finished tablet is able to disintegrate in water at 20 ° C within three minutes for a homogeneous drinkable 20 bar dispersion with a particle size of less than 0.71 mm. Compression-coated tablets according to claim 1, characterized in that the disintegrant is a cross-linked polyvinylpyrolidone. Compression-coated tablets according to claim 1, characterized in that the disintegrant is a cross-linked carboxylmethyl cellulose. Compression-coated tablets according to claim 1, characterized in that the disintegrant 30 is a sodium starch glycolate. Compression-coated tablets according to any one of the preceding claims, characterized in that the active compound (s) is present in the nucleus at a concentration not greater than 70% by weight. Compression-coated tablets according to claim 5, characterized in that the active substance in the core is cyclandelate. Compression-coated tablets according to claim 6, characterized in that the cyclandelate is present in the nucleus at a dose of 400-1200 mg per day. tablet. Compression-coated tablets according to claim 10, characterized in that the cyclandelate is present in the nucleus at a dose of 800 mg per day. tablet. Compression-coated tablets according to any one of the preceding claims, characterized in that their outer diameter is approx. 18 mm, their thickness 15 approx. 9 mm and their compressed coating is approx. 1.5 mm thick.